Muscular and Molecular Pathology Associated with SPATA5 Deficiency in a Child with EHLMRS

• Main Authors: Frederik Braun, Andreas Hentschel, Albert Sickmann, Theodore Marteau, Swantje Hertel, Fabian Förster, Holger Prokisch, Matias Wagner, Saskia Wortmann, Adela Della Marina, Heike Kölbel, Andreas Roos, Ulrike Schara-Schmidt
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: International Journal of Molecular Sciences
• Subjects: EHLMRS; SPATA5; mitochondrial disorder; muscle proteomics; myopathology
• Online Access: https://www.mdpi.com/1422-0067/22/15/7835

Mutations in the <i>SPATA5</i> gene are associated with epilepsy, hearing loss and mental retardation syndrome (EHLMRS). While <i>SPATA5</i> is ubiquitously expressed and is attributed a role within mitochondrial morphogenesis during spermatogenesis, there is only limited knowledge about the associated muscular and molecular pathology. This study reports on a comprehensive workup of muscular pathology, including proteomic profiling and microscopic studies, performed on an 8-year-old girl with typical clinical presentation of EHLMRS, where exome analysis revealed two clinically relevant, compound-heterozygous variants in <i>SPATA5</i>. Proteomic profiling of a quadriceps biopsy showed the dysregulation of 82 proteins, out of which 15 were localized in the mitochondrion, while 19 were associated with diseases presenting with phenotypical overlap to EHLMRS. Histological staining of our patient’s muscle biopsy hints towards mitochondrial pathology, while the identification of dysregulated proteins attested to the vulnerability of the cell beyond the mitochondria. Through our study we provide insights into the molecular etiology of EHLMRS and provide further evidence for a muscle pathology associated with SPATA5 deficiency, including a pathological histochemical pattern accompanied by dysregulated protein expression.